US2009137837A1PendingUtilityA1
Methods of synthesizing cinacalcet and salts thereof
Est. expiryJun 21, 2027(~0.9 yrs left)· nominal 20-yr term from priority
A61P 5/14C07C 209/22C07C 209/70A61P 3/00
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Claims
Abstract
Methods of preparing cinacalcet, cinacalcet derivatives, and salts thereof is disclosed herein. Also disclosed herein are polymorphs of cinacalcet, compositions of cinacalcet, and methods of treating a subject by administering cinacalcet, wherein cinacalcet is prepared by the disclosed methods.
Claims
exact text as granted — not AI-modified1 . A method for the preparation of cinacalcet or a salt thereof comprising:
a) admixing a compound of formula (I) and a compound of formula (II) under conditions that permit cross-metathesis to produce a compound of formula (III):
wherein each R 1 is the same or different and is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, OC 1 -C 6 alkyl, aryl, O-aryl, heteroaryl, and O-heteroaryl;
b) admixing compound (III) and 1-(1-naphthyl)ethylamine under conditions to permit allylic amination to produce a compound of formula (IV)
and
c) reducing compound (IV) under conditions that permit reduction to produce cinacalcet or a salt thereof.
2 . The method of claim 1 , wherein the conditions that permit cross-metathesis in step (a) comprise performing said cross-metathesis in the presence of a Ru catalyst.
3 . The method of claim 1 , wherein the conditions that permit allylic amination in step (b) comprise performing said allylic amination in the presence of a Pd, Ru, Ir, Pt, Rh, or Ni catalyst.
4 . The method of claim 1 , wherein the conditions that permit reduction in step (c) comprise performing said reduction in the presence of hydrogen and a Pd, Ni, Ir, Pt, Rh, or Ru catalyst.
5 . The method of claim 1 , wherein the product of said method is cinacalcet hydrochloride.
6 . A method for the preparation of cinacalcet or a salt thereof comprising:
a) admixing a compound of formula (V) and 1-(1-naphthyl)ethylamine under conditions to permit allylic amination to produce a compound of formulation (IV):
wherein R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl, C(O)C 1 -C 6 alkyl, C(O)aryl, C(O)heteroaryl, and C(O)OC 1 -C 6 alkyl; and
b) reducing compound (IV) under conditions that permit reduction to produce cinacalcet or a salt thereof.
7 . The method of claim 6 , further comprising
admixing 3-trifluoromethyl-benzaldehyde and a vinyl reagent to form a compound of formula (V).
8 . The method of claim 7 , wherein the vinyl reagent is selected from the group consisting of vinyl lithium and vinyl magnesium chloride.
9 . The method of claim 6 , wherein the conditions that permit allylic amination in step (a) comprise performing said allylic amination in the presence of a Pd catalyst.
10 . The method of claim 6 , wherein the conditions that permit reduction in step (b) comprise performing said reduction in the presence of hydrogen and a Pd, Ru, Ir, Pt, Rh, or Ni catalyst.
11 . The method of claim 6 , wherein the product of said method is cinacalcet hydrochloride.
12 . A method for the preparation of cinacalcet or a salt thereof comprising:
a) admixing a compound of formula (V), where R 2 is hydrogen, and 1-(1-naphthyl)ethyl isocyanate under conditions that permit the formation of a compound of formula (VI):
b) admixing compound (VI) and a catalyst under conditions that permit C—O to C—N rearrangement to form a compound of formula (IV)
and
c) reducing compound (IV) under conditions that permit reduction to produce cinacalcet or a salt thereof.
13 . The method of claim 12 , wherein the conditions that permit C—O to C—N rearrangement in step (b) comprise performing said C—O to C—N rearrangement in the presence of a metal catalyst, wherein the metal catalyst is selected from the group consisting of Pd, Ru, Ni, Ir, Rh, Hg, Au, and Pt.
14 . The method of claim 12 , wherein the conditions that permit reduction in step (c) comprise performing said reduction in the presence of hydrogen and a Pd, Ni, Pt, Rh, Ru, or Ir catalyst.
15 . The method of claim 12 , wherein the product of said method is cinacalcet hydrochloride.
16 . A method for the preparation of cinacalcet or a salt thereof comprising:
a) admixing 3-trifluoromethyl-cinnamic acid and 1-(1-naphthyl)ethylamine under conditions to permit amide bond formation to form a compound of formula (VIIB)
and
b) reducing compound (VIIB) under conditions that permit reduction to form cinacalcet or a salt thereof.
17 . The method of claim 16 , wherein the conditions that permit amide bond formation comprise performing said amide bond formation in the presence of a peptide coupling agent.
18 . The method of claim 17 , wherein the peptide coupling agent is selected from the group consisting of a chlorinating agent, a mixed anhydride, DIC, DCC, EDCI, CDI, HOBt, HOAt, pentafluorophenol, HBTU, HATU, and Mukaiyama's reagent.
19 . The method of claim 16 , wherein the conditions that permit reduction comprise (a) performing said reduction in the presence of hydrogen and a Pd, Ni, Ir, Pt, Rh, Ru or Ir catalyst, (b) performing said reducing in the presence of borane or lithium aluminum hydride, or (c) a combination thereof.
20 . The method of claim 16 , wherein the product of said method is cinacalcet hydrochloride.
21 .- 77 . (canceled)
78 . A compound of formula (IV)
79 . A compound of formula (VI)
80 . A compound of formula (VIIB)
81 . A compound of formula (XIII)
wherein R is hydrogen.
82 . A compound of formula (XVI)
wherein R is hydrogen.
83 . A compound of formula (XX)Join the waitlist — get patent alerts
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